KEGG   PATHWAY: oro04911
Entry
oro04911                    Pathway                                
Name
Insulin secretion - Odobenus rosmarus divergens (Pacific walrus)
Description
Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. Glucose-induced insulin secretion and its potentiation constitute the principal mechanism of insulin release. Glucose is transported by the glucose transporter (GLUT) into the pancreatic beta-cell. Metabolism of glucose generates ATP, which inhibits ATP-sensitive K+ channels and causes voltage-dependent Ca2+ influx. Elevation of [Ca2+]i triggers exocytotic release of insulin granules. Insulin secretion is further regulated by several hormones and neurotransmitters. Peptide hormones, such as glucagon-like peptide 1 (GLP-1), increase cAMP levels and thereby potentiate insulin secretion via the combined action of PKA and Epac2. Achetylcholine (ACh), a major parasympathetic neurotransmitter, binds to Gq-coupled receptors and activates phospholipase C- (PLC-), and the stimulatory effects involve activation of protein kinase C (PKC), which stimulates exocytosis. In addition, ACh mobilizes intracellular Ca2+ by activation of IP3 receptors.
Class
Organismal Systems; Endocrine system
Pathway map
oro04911  Insulin secretion
oro04911

Other DBs
GO: 0030073
Organism
Odobenus rosmarus divergens (Pacific walrus) [GN:oro]
Gene
101365014  SLC2A1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
101367009  SLC2A2; solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [KO:K07593]
101383256  GCK; glucokinase [KO:K12407] [EC:2.7.1.2]
101368019  TRPM4; transient receptor potential cation channel subfamily M member 4 [KO:K04979]
101379349  ATP1A2; sodium/potassium-transporting ATPase subunit alpha-2 [KO:K01539] [EC:7.2.2.13]
101379646  ATP1A4; sodium/potassium-transporting ATPase subunit alpha-4 [KO:K01539] [EC:7.2.2.13]
101376936  ATP1A3; sodium/potassium-transporting ATPase subunit alpha-3 isoform X1 [KO:K01539] [EC:7.2.2.13]
101366083  ATP1A1; sodium/potassium-transporting ATPase subunit alpha-1 isoform X1 [KO:K01539] [EC:7.2.2.13]
101368218  ATP1B3; sodium/potassium-transporting ATPase subunit beta-3 isoform X1 [KO:K01540]
101377129  ATP1B1; sodium/potassium-transporting ATPase subunit beta-1 [KO:K01540]
101376641  ATP1B4; protein ATP1B4 isoform X2 [KO:K01540]
101362729  ATP1B2; sodium/potassium-transporting ATPase subunit beta-2 [KO:K01540]
101382690  FXYD2; sodium/potassium-transporting ATPase subunit gamma isoform X2 [KO:K01538]
101366537  ABCC8; ATP-binding cassette sub-family C member 8 isoform X2 [KO:K05032]
101366830  KCNJ11; ATP-sensitive inward rectifier potassium channel 11 [KO:K05004]
101365624  CACNA1C; voltage-dependent L-type calcium channel subunit alpha-1C isoform X1 [KO:K04850]
101383514  CACNA1D; voltage-dependent L-type calcium channel subunit alpha-1D isoform X1 [KO:K04851]
101364481  CACNA1F; voltage-dependent L-type calcium channel subunit alpha-1F isoform X1 [KO:K04853]
101385947  CACNA1S; voltage-dependent L-type calcium channel subunit alpha-1S [KO:K04857]
101375584  CAMK2D; calcium/calmodulin-dependent protein kinase type II subunit delta [KO:K04515] [EC:2.7.11.17]
101375944  CAMK2A; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
101367567  CAMK2G; calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X2 [KO:K04515] [EC:2.7.11.17]
101384300  CAMK2B; calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
101374985  KCNMA1; calcium-activated potassium channel subunit alpha-1 isoform X1 [KO:K04936]
101373053  LOW QUALITY PROTEIN: potassium channel subfamily U member 1-like [KO:K05274]
101381979  KCNMB1; calcium-activated potassium channel subunit beta-1 [KO:K04937]
101371468  KCNMB2; calcium-activated potassium channel subunit beta-2 [KO:K04938]
101365723  KCNMB4; calcium-activated potassium channel subunit beta-4 [KO:K04941]
101370332  KCNN1; small conductance calcium-activated potassium channel protein 1 isoform X2 [KO:K04942]
101374769  KCNN2; small conductance calcium-activated potassium channel protein 2 isoform X1 [KO:K04943]
101374891  KCNN3; small conductance calcium-activated potassium channel protein 3 isoform X1 [KO:K04944]
101383222  KCNN4; intermediate conductance calcium-activated potassium channel protein 4 [KO:K04945]
101380721  GCG; glucagon [KO:K05259]
101366823  GLP1R; glucagon-like peptide 1 receptor [KO:K04581]
101364460  GIP; gastric inhibitory polypeptide [KO:K05258]
101383865  GPR119; glucose-dependent insulinotropic receptor [KO:K08424]
101383041  ADCYAP1; pituitary adenylate cyclase-activating polypeptide [KO:K05262]
101378697  ADCYAP1R1; pituitary adenylate cyclase-activating polypeptide type I receptor isoform X2 [KO:K04587]
101364060  GNAS; guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas isoform X1 [KO:K04632]
105757053  neuroendocrine secretory protein 55 [KO:K04632]
101379158  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101365382  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101368682  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101374313  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
101380824  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101373816  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
101377421  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101370350  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101364108  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101367408  PRKACB; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
101383001  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
101383024  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101374034  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101368122  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101383806  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101385783  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101376293  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
101381943  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
101385675  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101384862  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
101381436  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
101382101  PDX1; pancreas/duodenum homeobox protein 1 [KO:K07594]
101383590  INS; insulin [KO:K04526]
101382059  RAPGEF4; rap guanine nucleotide exchange factor 4 isoform X1 [KO:K04351]
101375940  RIMS2; regulating synaptic membrane exocytosis protein 2 isoform X4 [KO:K15297]
101381322  PCLO; protein piccolo [KO:K16882]
101372691  RAB3A; ras-related protein Rab-3A [KO:K07882]
101369318  CCKAR; cholecystokinin receptor type A [KO:K04194]
101362497  CHRM3; muscarinic acetylcholine receptor M3 [KO:K04131]
101370691  FFAR1; free fatty acid receptor 1 [KO:K04325]
101384596  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
101385358  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
101379806  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
101375710  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
101386162  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X2 [KO:K05858] [EC:3.1.4.11]
101386750  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101380808  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X2 [KO:K04960]
101372904  RYR2; ryanodine receptor 2 [KO:K04962]
101368222  ryanodine receptor 2-like [KO:K04962]
101381733  VAMP2; vesicle-associated membrane protein 2 isoform X1 [KO:K13504]
101371675  STX1A; syntaxin-1A [KO:K04560]
101380987  SNAP25; synaptosomal-associated protein 25 isoform X1 [KO:K18211]
101386060  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101380879  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101363254  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
Compound
C00002  ATP
C00022  Pyruvate
C00031  D-Glucose
C00076  Calcium cation
C00092  D-Glucose 6-phosphate
C00162  Fatty acid
C00165  Diacylglycerol
C00238  Potassium cation
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C01996  Acetylcholine
Reference
PMID:20551594
  Authors
Seino S, Shibasaki T, Minami K
  Title
Pancreatic beta-cell signaling: toward better understanding of diabetes and its treatment.
  Journal
Proc Jpn Acad Ser B Phys Biol Sci 86:563-77 (2010)
DOI:10.2183/pjab.86.563
Reference
PMID:20225132
  Authors
Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ
  Title
Regulation of insulin secretion: role of mitochondrial signalling.
  Journal
Diabetologia 53:1019-32 (2010)
DOI:10.1007/s00125-010-1685-0
Reference
PMID:22974438
  Authors
Rorsman P, Braun M
  Title
Regulation of insulin secretion in human pancreatic islets.
  Journal
Annu Rev Physiol 75:155-79 (2013)
DOI:10.1146/annurev-physiol-030212-183754
Reference
PMID:9715374
  Authors
Jones PM, Persaud SJ
  Title
Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells.
  Journal
Endocr Rev 19:429-61 (1998)
DOI:10.1210/edrv.19.4.0339
Reference
PMID:21934040
  Authors
MacDonald PE
  Title
Signal integration at the level of ion channel and exocytotic function in pancreatic beta-cells.
  Journal
Am J Physiol Endocrinol Metab 301:E1065-9 (2011)
DOI:10.1152/ajpendo.00426.2011
Reference
PMID:9914469
  Authors
Lang J
  Title
Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion.
  Journal
Eur J Biochem 259:3-17 (1999)
DOI:10.1046/j.1432-1327.1999.00043.x
Reference
PMID:10605628
  Authors
Kieffer TJ, Habener JF
  Title
The glucagon-like peptides.
  Journal
Endocr Rev 20:876-913 (1999)
DOI:10.1210/edrv.20.6.0385
Reference
PMID:19036624
  Authors
Girard J
  Title
The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions.
  Journal
Diabetes Metab 34:550-9 (2008)
DOI:10.1016/j.diabet.2008.09.001
Reference
PMID:15655710
  Authors
Holz GG
  Title
New insights concerning the glucose-dependent insulin secretagogue action of glucagon-like peptide-1 in pancreatic beta-cells.
  Journal
Horm Metab Res 36:787-94 (2004)
DOI:10.1055/s-2004-826165
Reference
PMID:15271645
  Authors
Holst JJ, Gromada J
  Title
Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans.
  Journal
Am J Physiol Endocrinol Metab 287:E199-206 (2004)
DOI:10.1152/ajpendo.00545.2003
Reference
PMID:17306374
  Authors
Doyle ME, Egan JM
  Title
Mechanisms of action of glucagon-like peptide 1 in the pancreas.
  Journal
Pharmacol Ther 113:546-93 (2007)
DOI:10.1016/j.pharmthera.2006.11.007
Reference
PMID:19074620
  Authors
Kim W, Egan JM
  Title
The role of incretins in glucose homeostasis and diabetes treatment.
  Journal
Pharmacol Rev 60:470-512 (2008)
DOI:10.1124/pr.108.000604
Reference
PMID:19817800
  Authors
Seino S, Takahashi H, Fujimoto W, Shibasaki T
  Title
Roles of cAMP signalling in insulin granule exocytosis.
  Journal
Diabetes Obes Metab 11 Suppl 4:180-8 (2009)
DOI:10.1111/j.1463-1326.2009.01108.x
Reference
PMID:22970724
  Authors
Tengholm A
  Title
Cyclic AMP dynamics in the pancreatic beta-cell.
  Journal
Ups J Med Sci 117:355-69 (2012)
DOI:10.3109/03009734.2012.724732
Reference
PMID:14693691
  Authors
Holz GG
  Title
Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell.
  Journal
Diabetes 53:5-13 (2004)
DOI:10.2337/diabetes.53.1.5
Reference
PMID:20055708
  Authors
Gloerich M, Bos JL
  Title
Epac: defining a new mechanism for cAMP action.
  Journal
Annu Rev Pharmacol Toxicol 50:355-75 (2010)
DOI:10.1146/annurev.pharmtox.010909.105714
Reference
PMID:17084085
  Authors
Bos JL
  Title
Epac proteins: multi-purpose cAMP targets.
  Journal
Trends Biochem Sci 31:680-6 (2006)
DOI:10.1016/j.tibs.2006.10.002
Reference
PMID:11522660
  Authors
Filipsson K, Kvist-Reimer M, Ahren B
  Title
The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function.
  Journal
Diabetes 50:1959-69 (2001)
DOI:10.2337/diabetes.50.9.1959
Reference
PMID:19817784
  Authors
Kebede MA, Alquier T, Latour MG, Poitout V
  Title
Lipid receptors and islet function: therapeutic implications?
  Journal
Diabetes Obes Metab 11 Suppl 4:10-20 (2009)
DOI:10.1111/j.1463-1326.2009.01114.x
Reference
PMID:19660440
  Authors
Morgan NG, Dhayal S
  Title
G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell.
  Journal
Biochem Pharmacol 78:1419-27 (2009)
DOI:10.1016/j.bcp.2009.07.020
Related
pathway
oro00020  Citrate cycle (TCA cycle)
oro04020  Calcium signaling pathway
KO pathway
ko04911   
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